Department of Pharmacy, Xiaoshan Hospital, Hangzhou, Zhejiang 311202, P.R. China.
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China.
Mol Med Rep. 2017 Dec;16(6):8691-8698. doi: 10.3892/mmr.2017.7707. Epub 2017 Oct 4.
Wound healing impairment is increasingly recognized to be a consequence of hyperglycemia‑induced dysfunction of endothelial precursor cells (EPCs) in type 2 diabetes mellitus (T2DM). Metformin exhibits potential for the improvement of endothelial function and the wound healing process. However, the underlying mechanisms for the observed beneficial effects of metformin application remain to be completely understood. The present study assessed whether metformin, a widely used therapeutic drug for T2DM, may accelerate wound closure in T2DM db/db mice. Genetically hyperglycemic db/db mice were used as the T2DM model. Metformin (250 mg/kg/day; intragastric) was administered for two weeks prior to EPC collection and wound model creation in db/db mice. Wound healing was evaluated by alterations in the wound area and the number of platelet endothelial cell adhesion molecule‑positive cells. The function of the isolated bone marrow‑derived EPCs (BM‑EPCs) was assessed by a tube formation assay. The number of circulating EPCs, and the levels of intracellular nitric oxide (NO) and superoxide (O2‑) were detected by flow cytometry. Thrombospondin‑1 (TSP‑1) expression was determined by western blot analysis. It was observed that treatment with metformin accelerated wound healing, improved angiogenesis and increased the circulating EPC number in db/db mice. In vitro, treatment with metformin reversed the impaired BM‑EPC function reflected by tube formation, and significantly increased NO production while decreasing O2‑ levels in BM‑EPCs from db/db mice. In addition, TSP‑1 expression was markedly attenuated by treatment with metformin in cultured BM‑EPCs. Metformin contributed to wound healing and improved angiogenesis in T2DM mice, which was, in part, associated with stimulation of NO, and inhibition of O2‑ and TSP‑1 in EPCs from db/db mice.
伤口愈合受损越来越被认为是 2 型糖尿病（T2DM）中高血糖诱导内皮祖细胞（EPCs）功能障碍的后果。二甲双胍具有改善内皮功能和伤口愈合过程的潜力。然而，二甲双胍应用的观察到的有益效果的潜在机制仍有待完全理解。本研究评估了广泛用于治疗 T2DM 的治疗药物二甲双胍是否可以加速 T2DM db/db 小鼠的伤口闭合。使用遗传高血糖 db/db 小鼠作为 T2DM 模型。在 db/db 小鼠中收集 EPC 和创建伤口模型之前，给予二甲双胍（250mg/kg/天；口服）治疗两周。通过改变伤口面积和血小板内皮细胞黏附分子阳性细胞的数量来评估伤口愈合。通过管形成测定评估分离的骨髓源性内皮祖细胞（BM-EPCs）的功能。通过流式细胞术检测循环 EPC 数量以及细胞内一氧化氮（NO）和超氧化物（O2-）的水平。通过 Western blot 分析测定血栓调节蛋白-1（TSP-1）的表达。结果观察到，二甲双胍治疗可加速 db/db 小鼠的伤口愈合，改善血管生成并增加循环 EPC 数量。在体外，二甲双胍治疗可逆转 BM-EPC 功能受损，表现为管形成，并且可显著增加 db/db 小鼠的 BM-EPC 中 NO 的产生，同时降低 O2-水平。此外，在培养的 BM-EPC 中，TSP-1 的表达明显被二甲双胍抑制。二甲双胍有助于 T2DM 小鼠的伤口愈合和血管生成，这部分与刺激 NO 和抑制 O2-和 TSP-1 在 db/db 小鼠的 EPCs 中有关。
